PROJECT SUMMARY In the era of combination antiretroviral therapy, routine care of persons living with HIV infection (PLWH) requires extra attention to coinfections and comorbidities, as PLWH with impaired immunologic competency (IIC) are prone to non-AIDS morbidity and mortality. We propose that IIC is also the basis for accelerated/ premature aging (A/PA) in PLWH and that herpes zoster (shingles) can serve as a readily diagnosed sentinel disease for studying molecular and immunologic correlates of A/PA. To prove these concepts, we have already gathered compelling data from a Southeast US cohort of PLWH (N = 4,225) to demonstrate that relatively young PLWH (30-55 years old) are already at high risk of developing herpes zoster, but recurrent herpes zoster is relatively rare. New research can now focus on the disparity between biological age and chronological age in PLWH and on the dynamics of immune protection against recurrent herpes zoster. Specifically, aim 1 will identify DNA methylation (epigenetic) age and molecular signatures of memory T-cells shortly before the onset of herpes zoster, using high-throughput techniques to define genome-wide DNA methylation and gene expression profiles. Aim 2 will compare virus-specific T-cell activation, proliferation and immune function after co-culture with pools of immunogens derived from the varicella-zoster virus, using samples from two visits after the first occurrence of herpes zoster. These studies will target two primary ethnic groups (African Americans and European Americans) with disparate HIV/AIDS burdens and will properly account for potential confounders (e.g., coinfections and comorbidities) as observed in a clinical setting. For further translation, analyses of DNA methylation age (aim 1) should help with the design and implementation of interventional strategies for alleviating or reversing IIC in diverse PLWH populations, including the application of a newly available recombinant vaccine (Shingrix) against herpes zoster.